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Mental ill-health has a major impact on young people, with pain often co-occurring. We estimated the prevalence and impact of pain in young people with mental ill-health.
Methods
Longitudinal data (baseline and three-month follow-up) of 1,107 Australian young people (aged 12–25 years) attending one of five youth mental health services. Multi-level linear mixed models estimated associations between pain characteristics (frequency, intensity, and limitations) and outcomes with false discovery rate (FDR) adjustment. Pain characteristics were baseline-centered to estimate if the baseline score (between-participant effect) and/or change from baseline (within-participant effect) was associated with outcomes.
Results
At baseline, 16% reported serious pain more than 3 days, 51% reported at least moderate pain, and 25% reported pain-related activity limitations in the last week. Between participants, higher serious pain frequency was associated with greater anxiety symptoms (β[95%CI]: 0.90 [0.45, 1.35], FDR-p=0.001), higher pain intensity was associated with greater symptoms of depression (1.50 [0.71, 2.28], FDR-p=0.001), anxiety (1.22 [0.56, 1.89], FDR-p=0.002), and suicidal ideation (3.47 [0.98, 5.96], FDR-p=0.020), and higher pain limitations were associated with greater depressive symptoms (1.13 [0.63, 1.63], FDR-p<0.001). Within participants, increases in pain intensity were associated with increases in tobacco use risk (1.09 [0.48, 1.70], FDR-p=0.002), and increases in pain limitations were associated with increases in depressive symptoms (0.99 [0.54, 1.43], FDR-p<0.001) and decreases in social and occupational functioning (−1.08 [−1.78, −0.38], FDR-p=0.009).
Conclusions
One-in-two young people seeking support for mental ill-health report pain. Youth mental health services should consider integrating pain management.
Objectives/Goals: We describe the prevalence of individuals with household exposure to SARS-CoV-2, who subsequently report symptoms consistent with COVID-19, while having PCR results persistently negative for SARS-CoV-2 (S[+]/P[-]). We assess whether paired serology can assist in identifying the true infection status of such individuals. Methods/Study Population: In a multicenter household transmission study, index patients with SARS-CoV-2 were identified and enrolled together with their household contacts within 1 week of index’s illness onset. For 10 consecutive days, enrolled individuals provided daily symptom diaries and nasal specimens for polymerase chain reaction (PCR). Contacts were categorized into 4 groups based on presence of symptoms (S[+/-]) and PCR positivity (P[+/-]). Acute and convalescent blood specimens from these individuals (30 days apart) were subjected to quantitative serologic analysis for SARS-CoV-2 anti-nucleocapsid, spike, and receptor-binding domain antibodies. The antibody change in S[+]/P[-] individuals was assessed by thresholds derived from receiver operating characteristic (ROC) analysis of S[+]/P[+] (infected) versusS[-]/P[-] (uninfected). Results/Anticipated Results: Among 1,433 contacts, 67% had ≥1 SARS-CoV-2 PCR[+] result, while 33% remained PCR[-]. Among the latter, 55% (n = 263) reported symptoms for at least 1 day, most commonly congestion (63%), fatigue (63%), headache (62%), cough (59%), and sore throat (50%). A history of both previous infection and vaccination was present in 37% of S[+]/P[-] individuals, 38% of S[-]/P[-], and 21% of S[+]/P[+] (P<0.05). Vaccination alone was present in 37%, 41%, and 52%, respectively. ROC analyses of paired serologic testing of S[+]/P[+] (n = 354) vs. S[-]/P[-] (n = 103) individuals found anti-nucleocapsid data had the highest area under the curve (0.87). Based on the 30-day antibody change, 6.9% of S[+]/P[-] individuals demonstrated an increased convalescent antibody signal, although a similar seroresponse in 7.8% of the S[-]/P[-] group was observed. Discussion/Significance of Impact: Reporting respiratory symptoms was common among household contacts with persistent PCR[-] results. Paired serology analyses found similar seroresponses between S[+]/P[-] and S[-]/P[-] individuals. The symptomatic-but-PCR-negative phenomenon, while frequent, is unlikely attributable to true SARS-CoV-2 infections that go missed by PCR.
Increasing daylight exposure might be a simple way to improve mental health. However, little is known about daylight-symptom associations in depressive disorders.
Methods
In a subset of the Australian Genetics of Depression Study (N = 13,480; 75% female), we explored associations between self-reported number of hours spent in daylight on a typical workday and free day and seven symptom dimensions: depressive (overall, somatic, psychological); hypo-manic-like; psychotic-like; insomnia; and daytime sleepiness. Polygenic scores for major depressive disorder (MDD); bipolar disorder (BD); and schizophrenia (SCZ) were calculated. Models were adjusted for age, sex, shift work status, employment status, season, and educational attainment. Exploratory analyses examined age-stratified associations (18–24 years; 25–34 years; 35–64 years; 65 and older). Bonferroni-corrected associations (p < 0.004) are discussed.
Results
Adults with depression reported spending a median of one hour in daylight on workdays and three hours on free days. More daylight exposure on workdays and free days was associated with lower depressive (overall, psychological, somatic) and insomnia symptoms (p’s<0.001), but higher hypo-manic-like symptoms (p’s<0.002). Genetic loading for MDD and SCZ were associated with less daylight exposure in unadjusted correlational analyses (effect sizes were not meaningful). Exploratory analyses revealed age-related heterogeneity. Among 18–24-year-olds, no symptom dimensions were associated with daylight. By contrast, for the older age groups, there was a pattern of more daylight exposure and lower insomnia symptoms (p < 0.003) (except for 25–34-year-olds on free days, p = 0.019); and lower depressive symptoms with more daylight on free days, and to some extent workdays (depending on the age-group).
Conclusions
Exploration of the causal status of daylight in depression is warranted.
Compared with other areas of mental health research that are focused on the active and early management of youth presenting in the early stages of major mental disorders, there has been a relative lack of focus on young people with emerging or established bipolar disorders. Recently, this has stimulated both international professional societies (e.g., International Society for Bipolar Disorders [ISBD] Early Intervention Task Force) and funding agencies from Canada, UK, Australia, and the USA – including the Daymark Foundation (Jain et al. 2023), Wellcome Trust (2022), National Health and Medical Research Council, and BD2 – to promote a focus on identifying the major challenges in this field and gathering support for novel research and clinical service programmes.
Accurate diagnosis of bipolar disorder (BPD) is difficult in clinical practice, with an average delay between symptom onset and diagnosis of about 7 years. A depressive episode often precedes the first manic episode, making it difficult to distinguish BPD from unipolar major depressive disorder (MDD).
Aims
We use genome-wide association analyses (GWAS) to identify differential genetic factors and to develop predictors based on polygenic risk scores (PRS) that may aid early differential diagnosis.
Method
Based on individual genotypes from case–control cohorts of BPD and MDD shared through the Psychiatric Genomics Consortium, we compile case–case–control cohorts, applying a careful quality control procedure. In a resulting cohort of 51 149 individuals (15 532 BPD patients, 12 920 MDD patients and 22 697 controls), we perform a variety of GWAS and PRS analyses.
Results
Although our GWAS is not well powered to identify genome-wide significant loci, we find significant chip heritability and demonstrate the ability of the resulting PRS to distinguish BPD from MDD, including BPD cases with depressive onset (BPD-D). We replicate our PRS findings in an independent Danish cohort (iPSYCH 2015, N = 25 966). We observe strong genetic correlation between our case–case GWAS and that of case–control BPD.
Conclusions
We find that MDD and BPD, including BPD-D are genetically distinct. Our findings support that controls, MDD and BPD patients primarily lie on a continuum of genetic risk. Future studies with larger and richer samples will likely yield a better understanding of these findings and enable the development of better genetic predictors distinguishing BPD and, importantly, BPD-D from MDD.
It is well established that there is a substantial genetic component to eating disorders (EDs). Polygenic risk scores (PRSs) can be used to quantify cumulative genetic risk for a trait at an individual level. Recent studies suggest PRSs for anorexia nervosa (AN) may also predict risk for other disordered eating behaviors, but no study has examined if PRS for AN can predict disordered eating as a global continuous measure. This study aimed to investigate whether PRS for AN predicted overall levels of disordered eating, or specific lifetime disordered eating behaviors, in an Australian adolescent female population.
Methods
PRSs were calculated based on summary statistics from the largest Psychiatric Genomics Consortium AN genome-wide association study to date. Analyses were performed using genome-wide complex trait analysis to test the associations between AN PRS and disordered eating global scores, avoidance of eating, objective bulimic episodes, self-induced vomiting, and driven exercise in a sample of Australian adolescent female twins recruited from the Australian Twin Registry (N = 383).
Results
After applying the false-discovery rate correction, the AN PRS was significantly associated with all disordered eating outcomes.
Conclusions
Findings suggest shared genetic etiology across disordered eating presentations and provide insight into the utility of AN PRS for predicting disordered eating behaviors in the general population. In the future, PRSs for EDs may have clinical utility in early disordered eating risk identification, prevention, and intervention.
Knowledge of sex differences in risk factors for posttraumatic stress disorder (PTSD) can contribute to the development of refined preventive interventions. Therefore, the aim of this study was to examine if women and men differ in their vulnerability to risk factors for PTSD.
Methods
As part of the longitudinal AURORA study, 2924 patients seeking emergency department (ED) treatment in the acute aftermath of trauma provided self-report assessments of pre- peri- and post-traumatic risk factors, as well as 3-month PTSD severity. We systematically examined sex-dependent effects of 16 risk factors that have previously been hypothesized to show different associations with PTSD severity in women and men.
Results
Women reported higher PTSD severity at 3-months post-trauma. Z-score comparisons indicated that for five of the 16 examined risk factors the association with 3-month PTSD severity was stronger in men than in women. In multivariable models, interaction effects with sex were observed for pre-traumatic anxiety symptoms, and acute dissociative symptoms; both showed stronger associations with PTSD in men than in women. Subgroup analyses suggested trauma type-conditional effects.
Conclusions
Our findings indicate mechanisms to which men might be particularly vulnerable, demonstrating that known PTSD risk factors might behave differently in women and men. Analyses did not identify any risk factors to which women were more vulnerable than men, pointing toward further mechanisms to explain women's higher PTSD risk. Our study illustrates the need for a more systematic examination of sex differences in contributors to PTSD severity after trauma, which may inform refined preventive interventions.
Understanding characteristics of healthcare personnel (HCP) with SARS-CoV-2 infection supports the development and prioritization of interventions to protect this important workforce. We report detailed characteristics of HCP who tested positive for SARS-CoV-2 from April 20, 2020 through December 31, 2021.
Methods:
CDC collaborated with Emerging Infections Program sites in 10 states to interview HCP with SARS-CoV-2 infection (case-HCP) about their demographics, underlying medical conditions, healthcare roles, exposures, personal protective equipment (PPE) use, and COVID-19 vaccination status. We grouped case-HCP by healthcare role. To describe residential social vulnerability, we merged geocoded HCP residential addresses with CDC/ATSDR Social Vulnerability Index (SVI) values at the census tract level. We defined highest and lowest SVI quartiles as high and low social vulnerability, respectively.
Results:
Our analysis included 7,531 case-HCP. Most case-HCP with roles as certified nursing assistant (CNA) (444, 61.3%), medical assistant (252, 65.3%), or home healthcare worker (HHW) (225, 59.5%) reported their race and ethnicity as either non-Hispanic Black or Hispanic. More than one third of HHWs (166, 45.2%), CNAs (283, 41.7%), and medical assistants (138, 37.9%) reported a residential address in the high social vulnerability category. The proportion of case-HCP who reported using recommended PPE at all times when caring for patients with COVID-19 was lowest among HHWs compared with other roles.
Conclusions:
To mitigate SARS-CoV-2 infection risk in healthcare settings, infection prevention, and control interventions should be specific to HCP roles and educational backgrounds. Additional interventions are needed to address high social vulnerability among HHWs, CNAs, and medical assistants.
Female fertility is a complex trait with age-specific changes in spontaneous dizygotic (DZ) twinning and fertility. To elucidate factors regulating female fertility and infertility, we conducted a genome-wide association study (GWAS) on mothers of spontaneous DZ twins (MoDZT) versus controls (3273 cases, 24,009 controls). This is a follow-up study to the Australia/New Zealand (ANZ) component of that previously reported (Mbarek et al., 2016), with a sample size almost twice that of the entire discovery sample meta-analysed in the previous article (and five times the ANZ contribution to that), resulting from newly available additional genotyping and representing a significant increase in power. We compare analyses with and without male controls and show unequivocally that it is better to include male controls who have been screened for recent family history, than to use only female controls. Results from the SNP based GWAS identified four genomewide significant signals, including one novel region, ZFPM1 (Zinc Finger Protein, FOG Family Member 1), on chromosome 16. Previous signals near FSHB (Follicle Stimulating Hormone beta subunit) and SMAD3 (SMAD Family Member 3) were also replicated (Mbarek et al., 2016). We also ran the GWAS with a dominance model that identified a further locus ADRB2 on chr 5. These results have been contributed to the International Twinning Genetics Consortium for inclusion in the next GWAS meta-analysis (Mbarek et al., in press).
Arid regions are especially vulnerable to climate change and land use. More than one-third of Earth's population relies on these ecosystems. Modern observations lack the temporal depth to determine vegetation responses to climate and human activity, but paleoecological and archaeological records can be used to investigate these relationships. Decreasing rainfall across the Late Holocene provides a case study for vegetation response to changing hydroclimate. Rock hyrax (Procavia capensis) middens preserve paleoenvironmental indicators in arid environments where traditional archives are unavailable. Pollen from modern middens collected in Dhofar, Oman, demonstrates the reliability of this archive. Pollen, stable isotope (δ13C, δ15N), and microcharcoal data from fossil middens reveal changes in vegetation, relative moisture, and fire from 4000 cal yr BP to the present. Trees limited to moister areas (e.g., Terminalia) today existed farther inland at ~3100 cal yr BP. After ~2900 cal yr BP, taxa with more xeric affiliations (e.g., Senegalia) had increased. Coprophilous fungal spores (Sporormiella) and grazing indicator pollen revealed an amplified signal of domesticate grazing at ~1000 cal yr BP. This indicates that trees associated with semiarid environments were maintained in the interior desert during ~3000–4000 yr of decreasing rainfall and that impacts of human activity intensified after the transition to a drier environment.
Several hypotheses may explain the association between substance use, posttraumatic stress disorder (PTSD), and depression. However, few studies have utilized a large multisite dataset to understand this complex relationship. Our study assessed the relationship between alcohol and cannabis use trajectories and PTSD and depression symptoms across 3 months in recently trauma-exposed civilians.
Methods
In total, 1618 (1037 female) participants provided self-report data on past 30-day alcohol and cannabis use and PTSD and depression symptoms during their emergency department (baseline) visit. We reassessed participant's substance use and clinical symptoms 2, 8, and 12 weeks posttrauma. Latent class mixture modeling determined alcohol and cannabis use trajectories in the sample. Changes in PTSD and depression symptoms were assessed across alcohol and cannabis use trajectories via a mixed-model repeated-measures analysis of variance.
Results
Three trajectory classes (low, high, increasing use) provided the best model fit for alcohol and cannabis use. The low alcohol use class exhibited lower PTSD symptoms at baseline than the high use class; the low cannabis use class exhibited lower PTSD and depression symptoms at baseline than the high and increasing use classes; these symptoms greatly increased at week 8 and declined at week 12. Participants who already use alcohol and cannabis exhibited greater PTSD and depression symptoms at baseline that increased at week 8 with a decrease in symptoms at week 12.
Conclusions
Our findings suggest that alcohol and cannabis use trajectories are associated with the intensity of posttrauma psychopathology. These findings could potentially inform the timing of therapeutic strategies.
To evaluate the effectiveness of an automated hand hygiene compliance system (AHHCS) audible alert and vibration for increasing hand hygiene compliance.
Design:
A nonrandomized, before-and-after, quasi-experimental study of an AHHCS was implemented in several inpatient units. Over a 51-day period, the system’s real-time audible alert was turned on, off, and back on. Overall, hand hygiene compliance was compared between days with activated and deactivated alerts and vibration.
Setting:
This study was conducted at a level 1 trauma center, a regional academic health system with 1,564 beds.
Participants:
The AHHCS was implemented in 9 inpatient units: 3 adult medical-surgical step-down units, and 6 adult intensive care units. The AHHCS badges were assigned to patient care assistants, registered nurses, physical therapists, occupational therapists, speech therapists, respiratory therapists, and physicians.
Intervention:
In the 9 inpatient units, selected healthcare staff were issued wearable badges that detected entry into and exit from a patient room. The audible alert was turned on for 16 days, turned off for 17 days, and then turned back on for 18 days, for a total of 51 days.
Results:
Utilization of the AHHCS real-time audible alert reminder resulted in sustained HH compliance ≥90%. When the alert and vibration were deactivated, HH compliance dropped to an average of 74% (range, 62%–78%). Once the alert resumed, HH compliance returned to ≥90%.
Conclusion:
Utilization of an AHHCS with real-time reminder audible alerts may be an effective method to increase healthcare worker HH compliance to ≥90%. Users of AHHCSs should consider the use of real-time reminders to improve HH compliance.
Subthreshold/attenuated syndromes are established precursors of full-threshold mood and psychotic disorders. Less is known about the individual symptoms that may precede the development of subthreshold syndromes and associated social/functional outcomes among emerging adults.
Methods
We modeled two dynamic Bayesian networks (DBN) to investigate associations among self-rated phenomenology and personal/lifestyle factors (role impairment, low social support, and alcohol and substance use) across the 19Up and 25Up waves of the Brisbane Longitudinal Twin Study. We examined whether symptoms and personal/lifestyle factors at 19Up were associated with (a) themselves or different items at 25Up, and (b) onset of a depression-like, hypo-manic-like, or psychotic-like subthreshold syndrome (STS) at 25Up.
Results
The first DBN identified 11 items that when endorsed at 19Up were more likely to be reendorsed at 25Up (e.g., hypersomnia, impaired concentration, impaired sleep quality) and seven items that when endorsed at 19Up were associated with different items being endorsed at 25Up (e.g., earlier fatigue and later role impairment; earlier anergia and later somatic pain). In the second DBN, no arcs met our a priori threshold for inclusion. In an exploratory model with no threshold, >20 items at 19Up were associated with progression to an STS at 25Up (with lower statistical confidence); the top five arcs were: feeling threatened by others and a later psychotic-like STS; increased activity and a later hypo-manic-like STS; and anergia, impaired sleep quality, and/or hypersomnia and a later depression-like STS.
Conclusions
These probabilistic models identify symptoms and personal/lifestyle factors that might prove useful targets for indicated preventative strategies.
Studying phenotypic and genetic characteristics of age at onset (AAO) and polarity at onset (PAO) in bipolar disorder can provide new insights into disease pathology and facilitate the development of screening tools.
Aims
To examine the genetic architecture of AAO and PAO and their association with bipolar disorder disease characteristics.
Method
Genome-wide association studies (GWASs) and polygenic score (PGS) analyses of AAO (n = 12 977) and PAO (n = 6773) were conducted in patients with bipolar disorder from 34 cohorts and a replication sample (n = 2237). The association of onset with disease characteristics was investigated in two of these cohorts.
Results
Earlier AAO was associated with a higher probability of psychotic symptoms, suicidality, lower educational attainment, not living together and fewer episodes. Depressive onset correlated with suicidality and manic onset correlated with delusions and manic episodes. Systematic differences in AAO between cohorts and continents of origin were observed. This was also reflected in single-nucleotide variant-based heritability estimates, with higher heritabilities for stricter onset definitions. Increased PGS for autism spectrum disorder (β = −0.34 years, s.e. = 0.08), major depression (β = −0.34 years, s.e. = 0.08), schizophrenia (β = −0.39 years, s.e. = 0.08), and educational attainment (β = −0.31 years, s.e. = 0.08) were associated with an earlier AAO. The AAO GWAS identified one significant locus, but this finding did not replicate. Neither GWAS nor PGS analyses yielded significant associations with PAO.
Conclusions
AAO and PAO are associated with indicators of bipolar disorder severity. Individuals with an earlier onset show an increased polygenic liability for a broad spectrum of psychiatric traits. Systematic differences in AAO across cohorts, continents and phenotype definitions introduce significant heterogeneity, affecting analyses.
The National Institute for Health and Care Excellence (NICE) worked with patients and staff from six patient organizations to review existing health technology assessment (HTA) methods and coproduce proposals to improve the following: patient involvement, how patient evidence is identified and considered by committees, and the support offered to patient stakeholders. This engagement identified important factors that HTA bodies need to understand to enable meaningful patient and public involvement (PPI), such as having clearly documented processes, appropriate evidence submission processes, transparent decisions, and suitable support. This work demonstrated the benefits of HTA bodies working collaboratively with patient stakeholders to improve PPI. By doing so, HTA bodies can increase their knowledge and understanding of the barriers faced by patient stakeholders to develop appropriate solutions to remove them. The coproduction approach improved stakeholder engagement methods, provided a better analysis of data, supported the development of meaningful conclusions, and improved stakeholder relationships.
In recent years, a variety of efforts have been made in political science to enable, encourage, or require scholars to be more open and explicit about the bases of their empirical claims and, in turn, make those claims more readily evaluable by others. While qualitative scholars have long taken an interest in making their research open, reflexive, and systematic, the recent push for overarching transparency norms and requirements has provoked serious concern within qualitative research communities and raised fundamental questions about the meaning, value, costs, and intellectual relevance of transparency for qualitative inquiry. In this Perspectives Reflection, we crystallize the central findings of a three-year deliberative process—the Qualitative Transparency Deliberations (QTD)—involving hundreds of political scientists in a broad discussion of these issues. Following an overview of the process and the key insights that emerged, we present summaries of the QTD Working Groups’ final reports. Drawing on a series of public, online conversations that unfolded at www.qualtd.net, the reports unpack transparency’s promise, practicalities, risks, and limitations in relation to different qualitative methodologies, forms of evidence, and research contexts. Taken as a whole, these reports—the full versions of which can be found in the Supplementary Materials—offer practical guidance to scholars designing and implementing qualitative research, and to editors, reviewers, and funders seeking to develop criteria of evaluation that are appropriate—as understood by relevant research communities—to the forms of inquiry being assessed. We dedicate this Reflection to the memory of our coauthor and QTD working group leader Kendra Koivu.1
This is the first report on the association between trauma exposure and depression from the Advancing Understanding of RecOvery afteR traumA(AURORA) multisite longitudinal study of adverse post-traumatic neuropsychiatric sequelae (APNS) among participants seeking emergency department (ED) treatment in the aftermath of a traumatic life experience.
Methods
We focus on participants presenting at EDs after a motor vehicle collision (MVC), which characterizes most AURORA participants, and examine associations of participant socio-demographics and MVC characteristics with 8-week depression as mediated through peritraumatic symptoms and 2-week depression.
Results
Eight-week depression prevalence was relatively high (27.8%) and associated with several MVC characteristics (being passenger v. driver; injuries to other people). Peritraumatic distress was associated with 2-week but not 8-week depression. Most of these associations held when controlling for peritraumatic symptoms and, to a lesser degree, depressive symptoms at 2-weeks post-trauma.
Conclusions
These observations, coupled with substantial variation in the relative strength of the mediating pathways across predictors, raises the possibility of diverse and potentially complex underlying biological and psychological processes that remain to be elucidated in more in-depth analyses of the rich and evolving AURORA database to find new targets for intervention and new tools for risk-based stratification following trauma exposure.
Molecular weight (Mw) effects in poly(vinylidene fluoride) (PVDF) influence both processability and combustion behavior in energetic Al–PVDF filaments. Results show decreased viscosity in unloaded and fuel-lean (i.e., 15 wt% Al) filaments. In highly loaded filaments (i.e., 30 wt% Al), reduced viscosity is minimal due to higher electrostatic interaction between Al particles and low Mw chains as confirmed by Fourier-transform infrared spectroscopy. Thermal and combustion analysis further corroborates this story as exothermic activity decreases in PVDF with smaller Mw chains. Differential scanning calorimetry and Thermogravimetric analysis show reduced reaction enthalpy and lower char yield in low Mw PVDF. Enthalpy reduction trends continued in nonequilibrium burn rate studies, which confirm that burn rate decreases in the presence of low Mw PVDF. Furthermore, powder X-ray patterns of post-burn products suggest that low Mw PVDF decomposition creates a diffusion barrier near the Al particle surface resulting in negligible AlF3 formation in fuel-rich filaments.
The pan-Canadian Oncology Drug Review (pCODR) evaluates new cancer drugs for public funding recommendations. While pCODR's deliberative framework evaluates overall clinical benefit and includes considerations for exceptional circumstances, rarity of indication is not explicitly addressed. Given the high unmet need that typically accompanies these indications, we explored the impact of rarity on oncology HTA recommendations and funding decisions.
Methods
We examined pCODR submissions with final recommendations from 2012 to 2017. Incidence rates were calculated using pCODR recommendation reports and statistics from the Canadian Cancer Society. Indications were classified as rare if the incidence rate was lower than 1/100,000 diagnoses, a definition referenced by the Canadian Agency for Drugs and Technologies in Health. Each pCODR final report was examined for the funding recommendation/justification, level of supporting evidence (presence of a randomized control trial [RCT]), and time to funding (if applicable).
Results
Of the ninety-six pCODR reviews examined, 16.6 percent were classified as rare indications per above criteria. While the frequency of positive funding recommendations were similar between rare and nonrare indication (78.6 vs. 75 percent), rare indications were less likely to be presented with evidence from RCT (50 vs. 90 percent). The average time to funding did not differ significantly across provinces.
Conclusion
Rare indications appear to be associated with weaker clinical evidence. There appears to be no association between rarity, positive funding recommendations, and time to funding. Further work will evaluate factors associated with positive recommendations and the real-world utilization of funded treatments for rare indications.
Previous genetic association studies have failed to identify loci robustly associated with sepsis, and there have been no published genetic association studies or polygenic risk score analyses of patients with septic shock, despite evidence suggesting genetic factors may be involved. We systematically collected genotype and clinical outcome data in the context of a randomized controlled trial from patients with septic shock to enrich the presence of disease-associated genetic variants. We performed genomewide association studies of susceptibility and mortality in septic shock using 493 patients with septic shock and 2442 population controls, and polygenic risk score analysis to assess genetic overlap between septic shock risk/mortality with clinically relevant traits. One variant, rs9489328, located in AL589740.1 noncoding RNA, was significantly associated with septic shock (p = 1.05 × 10–10); however, it is likely a false-positive. We were unable to replicate variants previously reported to be associated (p < 1.00 × 10–6 in previous scans) with susceptibility to and mortality from sepsis. Polygenic risk scores for hematocrit and granulocyte count were negatively associated with 28-day mortality (p = 3.04 × 10–3; p = 2.29 × 10–3), and scores for C-reactive protein levels were positively associated with susceptibility to septic shock (p = 1.44 × 10–3). Results suggest that common variants of large effect do not influence septic shock susceptibility, mortality and resolution; however, genetic predispositions to clinically relevant traits are significantly associated with increased susceptibility and mortality in septic individuals.